This Small Business Innovation Research (SBIR) Phase I application is in response to Funding Opportunity Announcement PA-12-088. Tumor-stromal interactions are increasingly recognized as critical components of the progression of human neoplasias, including tumor invasion and metastasis. Utilizing a novel high- throughput screening approach developed by the applicants, compounds will be identified having superior anti- myeloma activity in the presence of bone marrow stromal cells. This system more closely replicates the interactions of tumors and non-malignant tissues in patients, allowing the discovery of more clinically effective therapeutics compared to cell autonomous approaches. This proposal, in collaboration with the Conrad Prebys Center for Chemical Genomics (CPCCG) at Sanford-Burnham Medical Research Institute, focuses on screening a large compound collection against multiple myeloma cancer cell lines in the presence and absence of non-malignant bone marrow stromal cells to identify compounds with superior activity in a tumor microenvironment context. Probes will be further evaluated against a larger panel of tumors and non-malignant stromal cells to examine their broader activity. This technology and approach is a revolutionary advancement over current cell autonomous systems and has the potential to identify new first-in-class, FDA-approved and marketed drugs missed using conventional drug discovery approaches.